Arsine derivatives



Patented July 25, 2950 i I 'Eli 'Lilly and lGompany, Indianapolis, Ind., a

" corporation ofilndiana i j j No llrawingll'llm lication November 17, 1947,

Serial No. 786,551

I 45 Claims. (Cl.260440) My invention relates to derivatives of p-carbamidophenylarsine, and more particularly to those derivatives in which two organic radicals are attached to the arsenic atom through sulfur atoms.

The compounds of my invention, which may be called arsines, havefthe general formula I wherein R represents a methylene or an o-phenyleneradical and Rirepresents hydrogen, a metallic ora metalline radical. In'the. formof their acids, the above-represented arsine compounds are white or substantially white amorphous solids and have indefinite melting points. The metal salts of the acids, with few exceptions, likewise are white compounds-of indefinite melting points. Salts prepared from the'c'ommon metals of low molecular weight, for example the sodium, potassium and calcium salts, are water-soluble as are the salts formed from metalline radicals such as the ammonium and substituted ammonium radicals. 1

My novel compounds may and isolated in their acid form as follows: A mixture of a thiol derivative, 1. e., thiosalicylic or thioglycolic acid, and about one half of an equivalent of carbarsone oxide (prepared by the method of Doak et al., J. Am. Chem. soc. 62, 3013, 1940), is suspended in an aqueous's'olution containing a reagent having alkaline properties, for example, a water-soluble metal hydroxide, carbonate or bicarbonate. The aqueous suspension is heated until the thiol derivative has reacted with the carbarsone oxide and the reaction is complete. The reaction mixture is then cooled to room temperature and the desired-reaction product is precipitated from the solution bythe addition of. an acid such as any strong organic or mineral acid which will not yield a precipitate with the metal ion of the alkaline reagent used in ,the reaction. The precipitated materiahwhich is the desired arsine compound, "is separatedby filtration, and dried;

The salts of the new arsine compounds may be prepared by the methods known to the art, for example, by treating";agsuspension of the acid form of the compound in water with an aqueous readily be prepared ter-insoluble salts so prepared may be isolated by filtration, and water-soluble salts may be isolated by evaporating the aqueous solution to dry-'- ness.

The compounds of my invention are effective amebicides and are of value in the treatment of amebic dysentery and other protozoan-caused diseases. For such purpose they may be administered orally either in acid or salt form. My compounds are of the same order of in vitro activity as the alkaloid emetine which is widely used in the treatment of amebiasis despite its high toxicity and the deleterious side effects resulting ,from its use. In comparison with emetine, my compounds are not only more readily available, but are far less toxic and injurious to the patient receiving treatment. My compounds possess marked advantages over carbarsone in that they possess greater efiectiveness but cause no appreciable irritation of the gastric mucosa or the peritoneum. Oral administration of my compounds to individuals infected withEndamoebo-histolytied, the causative agent of amebiasis, has resultedin prompt disappearance of the organism and relief from clinical symptoms.

The following specific examples illustrate more fully the preparation of the compounds of my invention.

EXAMPLE 1 Pireparatz'on of di-(z carboxyphenylthz'o) -p-cdrb- I umidophenylarsine 42 g. of sodium bicarbonateare dissolved in one liter of water. 81 g. of thiosalicylic acid (of 92 percent purity) and 56.5 g. of carbarsone oxide 'are addedand'th'e mixture is-heated on a steam bath for 30 minutes. The reaction mixture is then cooled and filtered to remove a small amount of insoluble material. The filtrate is diluted with about GOO-cc. of water and is acidifiedwith concentrated hydrochloric'acid. The precipitate of di '(2 carboxyphenylthio) p-carbamidophenylarsine in practically quantitative yield which results, is filtered voff and washed well with water. The. material may be purified by dissolving it in sodium bicarbonate solution and reprecipitating it with: hydrochloric acid. The precipitate is separated by filtration, washed. with waterand dried solution or an equivalentiamount ofi-.alka1i. Wa .60 at about 1 1.

3 The reaction whereby the di-(2-carboxyphenylthio) -p-carbamidophenylarsine is formed may be represented by the following equation:

SCHaCOONa R 5 g L HiN- NAs 0 H u I SCHzCOONa +2 H o H soruoooNa II I H01 H:NC-N As II 0 somooom u 1 0? somooon i I HzN-C- As\ 1 1 s- "515v scrucoon I 5 1.v ,Acompound selected from the class consist- C-ONa 2n ing'of viii-1!2-.carbozwphenylthio) p carbamidophenylarsine; di-(carboxymethylthio) -p-carbamg iqophenylarsine, .and the sodium, potassium,

' calcium and ammonium salts there of.

2. Di- (2 carboxyphenylthio) p carbamidoph'enylarsine represented by the following for- I mula I f o I S HM d-NHQA'S 0 a s g I o,o11 1 i o o a o .H s

IIHINLIIgAL I 3.121 -,(carbqxymethylthio),-p-oarbamidophen- I jyl'arsinerepresented by the followin formula I I earnt-.011 I o Hm+tm1 as gpi-"(g earboiqiphenylthio), V-pwamamidQphen- 5 e I fi' arsine sq prepared weighed about 135 g. and contained. about M115, percent arsenic as compared with atheoretic'al amount of 14.51 percent.

The sodium salt of di (2-carloozzyphenylthio) p-carbamidophenylarsine is prepared by treating an aqueous suspension of the arsine with an equivalent" amount of-socliumbicarbonate and evaporatingthe solution to dryness. The-sodium salt thus prepared is a substantially White solid.

i 12.1 gr of thioglycolic acid and 100 g; of earbarsone oxide are :reaoteddn. a solution of 128 g. of sodiumibiearbonate in 2- liters .of water, according to -thei proceduredescribeddn Example 1-. 1 On treating the reaction mixture. with acid, (11- (car- 4.' The disodium salt of"di-=(2-carboxy-phenylthio) -p 'carbamidophenylarsine represented 'by the following formula O ife-ON?! 5. 'Ilhe d'isodi um salt of di-(carboxymethylthiol p -carbamidophenylarsine represented by the following formula boxymethylthio)-p-oarbamidophenylarsiner .pre-

Ioipitates; and isseparatedby filtration and dried. N

Di (carboxymethylthio) -p -.carbamidophena ylars'inethus prepared-was obtained. as a white AS amorphous solid,.solub1e in dilute. alkali. It consome-0m tai-ned about 19.65 percent of arsenicas compared 1 a g with theloaloulated amount of 19.119 percent.

TI'he reaction .=whereb .the di- (carboxymethylwEwAmWRGHRMANN.

th-io) .p-earbamidophenylarsineis formed may be represented by the following equation: 1 I ufilwflenmlon fifimg me 6 REFERENCES CITED OTHER REFERENCES Th followin references are of record in the Cohen et al., J. Chem. Soc. (London) v01. file of this patent: 1931, pages 3043-3057.

UNITE TA PA'I'ENTS Doak et al., J. Am. Chem. Soc., vol. 62, (1940), Number Name Date 5 pages 3012-3013 1,677,392 Kharasch July 17, 1928 2,331,833 Hamilton Oct. 12, 1943 

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF A DI-(2-CARBOXYPHENYLTHIO) - P - CARBAMIDOPHENYLARSINE, DI-(CARBOXYMETHYLHIO)-P-CARBAMIDOPHENYLARSINE, AND THE SODIU, POTASSIUM, CALCIUM AND AMMONIUM SALTS THEREOF. 